International Journal of Hematology

, Volume 96, Issue 4, pp 492–500

Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis

  • Yuhei Kamada
  • Mamiko Sakata-Yanagimoto
  • Masashi Sanada
  • Aiko Sato-Otsubo
  • Terukazu Enami
  • Kazumi Suzukawa
  • Naoki Kurita
  • Hidekazu Nishikii
  • Yasuhisa Yokoyama
  • Yasushi Okoshi
  • Yuichi Hasegawa
  • Seishi Ogawa
  • Shigeru Chiba
Original Article

Abstract

Single-nucleotide polymorphism genotyping microarray (SNP array) analysis provides detailed information on chromosomal copy number aberrations. To obtain detailed information on genomic abnormalities related to pathogenesis or prognosis of multiple myeloma (MM), we performed 250K SNP array analysis in 39 MM patients and 11 cell lines. We identified an accumulation of deletions and uniparental disomies at 22q12.1. Among the hyperdiploid MM cases, chromosomal imbalance at this locus was associated with poor prognosis. On sequencing, we also found a mutation in the seizure-related 6 homolog (mouse)-like (SEZ6L) gene located at ch.22q12.1 in an MM cell line, NOP1. We further found isolated deletions in 17 genes, five of which are known tumor suppressor genes. Of these, deletion of protein tyrosine phosphatase, receptor type D (PTPRD) was found in three samples, including two patients. Consistent with previous reports, non-hyperdiploid MM, deletion of 13q (del13q) and gain of 1q in non-hyperdiploid MMs were predictive of poor prognosis (p = 0.039, p = 0.049, and p = 0.013, respectively). However, our analysis revealed that unless accompanied by gain of 1q, the prognosis of non-hyperdiploid MM was as good as that of hyperdiploid MM. Thus, SNP array analysis provides significant information useful to understanding the pathogenesis and prognosis of MM.

Keywords

Multiple myeloma Snp array Chromosomal copy number imbalances 

Supplementary material

12185_2012_1171_MOESM1_ESM.eps (46.5 mb)
Supplemental Figure 1. Chromosomal copy number changes in 39 MM patientsFor each sample, amplified regions are shown as red lines above the chromosomes and loss of heterozygosity as green lines below the chromosomes. Each chromosome number is shown in the upper left corner(EPS 47593 kb)
12185_2012_1171_MOESM2_ESM.eps (46.5 mb)
Supplemental Figure 2. Mutation analysis of SEZ6L in MM patients and MM cell lines(a) The yellow lines show the loci of UPD. The minimal overlapping part of 22q12.1 is shown by the vertical pink line. The red arrow indicates SEZ6L. (b) NOP1 has the G563A mutation in exon2 of SEZ6L. This mutation causes alteration of arginine (R) to glutamine (Q). The mutation site is underlined in black and indicated by the red arrow. (c) Effect of the status of the 22q12.1 region on non-hyperdiploid MM. (d) Effect of the status of the 22q12.1 region on hyperdiploid MM. Deletion or UPD of this region results in worse prognosis in hyperdiploid MM (p = 0.040)(EPS 47648 kb)
12185_2012_1171_MOESM3_ESM.eps (39.2 mb)
Supplemental Figure 3. Small deleted regions containing tumor suppressor genesThe red or blue arrows indicate the deleted regions. The chromosomes are shown above and the patient’s number and SNP array data, below. (a) Loss of heterozygosity of PPP2R2B located at 5q32. (b) Loss of heterozygosity of DLG2 (red arrow) and BRCC2 (blue arrow) located at 11q14.1 and 11q24.1, respectively. (c) Loss of heterozygosity of PTPRT located at 20q13.2(EPS 40138 kb)
12185_2012_1171_MOESM4_ESM.eps (35.1 mb)
Supplemental Figure 4. Effect of 15q and 19q gain on overall survivalOverall survival tended to be better in MM patients who had either 15q gain or 19q gain, although the difference was not statistically significant for either(EPS 35925 kb)
12185_2012_1171_MOESM5_ESM.doc (124 kb)
Supplementary material 5 (DOC 124 kb)

Copyright information

© The Japanese Society of Hematology 2012

Authors and Affiliations

  • Yuhei Kamada
    • 1
  • Mamiko Sakata-Yanagimoto
    • 2
  • Masashi Sanada
    • 3
  • Aiko Sato-Otsubo
    • 3
  • Terukazu Enami
    • 1
  • Kazumi Suzukawa
    • 2
  • Naoki Kurita
    • 2
  • Hidekazu Nishikii
    • 2
  • Yasuhisa Yokoyama
    • 2
  • Yasushi Okoshi
    • 2
  • Yuichi Hasegawa
    • 2
  • Seishi Ogawa
    • 3
  • Shigeru Chiba
    • 2
  1. 1.Department of Hematology, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
  2. 2.Department of Hematology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  3. 3.Cancer Genomics PojectUniversity of TokyoTokyoJapan

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